This invention was supported in part by Grant No. DMR-72-03021-A04 from the National Science Foundation.
This invention relates to a new series of hexahydrobenzazocine derivatives characterized by a 1,6-methano group.
Analgesic agents have been widely used for thousands of years but many of the potentially most valuable known analgesic agents, e.g., morphine and codeine, exhibit excellent analgesic activity in combination with undesirable addictive properties.
Since in general compounds which show analgesic activity with no physical dependence liability also show narcotic antagonist properties, many analgesics which are also narcotic antagonists have not attained practical utility because of the powerful psychotomimetic effects on the central nervous system which are usually associated with powerful antagonist activity. The compounds of the present invention, however, appear to have a unique combination of properties in being strong analgesics without either physical dependence liability or narcotic antagonist properties.
Hexahydrobenzazocines having mild analgesic properties are described in Canadian Pat. No. 884,889, the contents of which are incorporated by reference herein. A number of compounds belonging to the benzomorphan system have been described by E. L. May and J. G. Murphy in J. Org. Chem. 20:257(1955) and by many subsequent workers, e.g., see A. E. Jacobson, Structure Activity Relationships of Analgesics and their Antagonists in "Handbook of Psychopharmacology," L. L. Iversen, S. D. Iversen and S. H. Snyder, ed., Plenum Publ. Corp. (1976).
The benzomorphans are benzazocines which are bridged by a 2,6-methylene group to form a tricyclic structure from the bicyclic structure of the parent benzazocine compounds. Rogers, et al in J. Med. Chem. 18(10):1036-1038 (1975) notes that the extra ring of the benzomorphans imposes a degree of conformational rigidity not found in the more flexible benzazocines and suggests that this decreased conformational flexibility may be primarily responsible for the increased binding energy between benzomorphans and the opiate receptor as compared to the benzazocines. While not wishing to be bound by the theory of the invention, it is believed that the more symmetrical 1,6-methano group of the compound in accordance with this invention may have a similar effect.
Chang, et al, in J. Med. Chem. 14(10): 1011(1971) describe the synthesis of 3-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-3-benzazocines. However, none of the reported compounds showed analgesic activity in the standardized tail pinch test and three compounds caused convulsions in the test animals.
Michne, et al, in J. Med. Chem. 15(12):1278(1972) reported a series of 2,6-methano-3-benzazocine derivatives. The compounds all have an oxygenfunction (keto or hydroxyl group) in the 1-position and exhibited both agonist and antagonish activity.
Mokotoff et al, In J. Hetero. Chem. 7:773(Aug. 1970) described B-norbenzomorphans or 1,5-methano-2,3,4,5-tetrahydro1H-2-benzazepines in which the nitrogen atom of a seven-membered heterocyclic ring is directly attached to a benzylic carbon atom and the heterocyclic ring is fused to a benzene ring. While these compounds lack the "central" carbon atom occurring in almost all of the known analgesics having morphine-like activity, the analgesic activities reported were less active and more toxic than the comparable 6,7-benzomorphans. A comparison of the methoxy analogues of B-norbenzomorphans surprisingly shows more analegesic activity than the corresponding 6,7-benzomorphans; see Jacobson et al., J. Med. Chem. --:7 (1970).
Sallay, U.S. Pat No. 3,819,614 and Takeda et al, J. Med. Chem. --(4): 630 (1970) describe 2,7-methano-3H-3-benzazonines in which the benzene ring is fused to a nine-membered heterocyclic ring. In conformity with past experience, these analgesic compounds are characterized by the nitrogen atom in the heterocyclic ring sharing the "central" carbon atom with the benzylic group, in common with most known analgesics having morphine-like activity.